Field of the Invention
The present invention relates to a method of preparing .alpha.-L-aspartyl-L-phenylalanine methyl ester (hereinafter referred to as ".alpha.-APM") which is useful as a sweetener and relates to an improved method of .alpha.-APM crystallization from a solution of .alpha.-APM.
Discussion of the Background
.alpha.-APM of the present invention is a dipeptide sweetener having a sweetness about 200 times that of sucrose (cane sugar). Because of its good quality sweetness and the low calorie content, it is widely used as a diet sweetener, and the worldwide demand for it is estimated to be over 10,000 tons by 1995.
.alpha.-APM is produced industrially by several methods. One method of obtaining .alpha.-APM is to react an N-substituted aspartic acid anhydride and a phenylalanine methyl ester in an organic solvent followed by removal of the N-substituent from the product by a conventional method (U.S. Pat. No. 3,786,039). The thus formed .alpha.-APM containing impurities is brought into contact with a hydrohalogenic acid to obtain .alpha.-APM hydrohalide, which is neutralized to obtain .alpha.-APM. A second method of obtaining .alpha.-APM is to methyl-esterify .alpha.-L-aspartyl-L-phenylalanine in a mixed solvent comprising water, methanol and hydrochloric acid to obtain .alpha.-APM hydrochloride, and then neutralize the hydrochloride to obtain .alpha.-APM (Japanese Patent Application Laid-Open No. 53-82752). A third method of obtaining .alpha.-APM is to condense an N-substituted aspartic acid and a phenylalanine methyl ester in the presence of an enzyme and thereafter remove the N-substituent from the product (Japanese Patent Application Laid-Open No. 53-135595).
In all of the above-mentioned methods, .alpha.-APM is finally crystallized by cooling from an aqueous solution having a relatively high temperature, then the resulting .alpha.-APM crystals are separated and dewatered in a solid-liquid separator, such as a centrifugal separator, and thereafter the thus separated crystals are dried. The cooling crystallization is generally carried out in a stirring crystallizer having a heat transfer surface for cooling or in a crystallizer equipped with an external heat exchanger and an external circulation system, such as pumps.
When crystallization of .alpha.-APM is carried out by cooling an .alpha.-APM-containing solution in a conventional forced flow system crystallizer with a stirring means or external circulation means, the solution always gives fine needle-like .alpha.-APM crystals having poor filterability and dewaterability. In addition, in such a system, numerous crystals precipitate and consolidate on the cooling heat transfer surface, whereby the heat transfer efficiency is markedly lowered. Therefore, to remove the consolidated crystal scale the operation of the crystallizer must be frequently stopped.
As a means of overcoming this problem, there is known a method of cooling an aqueous solution of .alpha.-APM by conductive heat transfer without effecting any forced flow such as mechanical stirring, to form a pseudo solid phase, optionally followed by further cooling the system (Japanese Patent Application Laid-Open No. 58-177952). In accordance with this method, peeling of the crystals from the cooling surface is extremely easy when discharging the crystal layer (sherbet-like pseudo solid phase), and .alpha.-APM crystals having improved filterability and dewaterability in the successive solid-liquid separation step can be obtained. However, where existing or widely-used crystallization equipment is employed, the cooling takes a long time, the efficiency of the method is poor. The discharge causes frequent problems when the method is used with a conventional tank type crystallizer.
A need continues to exist for a means of overcoming the above-mentioned problems in the .alpha.-APM crystallization step, i.e., preventing the crystals from forming on the heat transfer surface, decreasing investment in equipment by using an existing or widely-used crystallizer and improving the solid-liquid separability of the crystal slurry.